GPR4 knockout improves renal ischemia–reperfusion injury and inhibits apoptosis via suppressing the expression of CHOP

Dong, Biao; Zhang, Xiaolu; Fan, Yafeng; Cao, Shengli; Zhang, Xuepei

doi:10.1042/bcj20170676

Cited by 23 publications

(14 citation statements)

References 31 publications

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“…A recent study demonstrated that GPR4 deficiency improved renal ischemia-reperfusion injury clinical parameters such as survival rate, serum creatinine, and blood urea nitrogen levels. Furthermore, genetic deficiency of GPR4 deterred apoptosis by suppressing CHOP expression in the kidney [21]. This study is consistent with our previous report demonstrating CHOP expression is dependent on GPR4 activation in HUVECs [5,6].…”

Section: Discussionsupporting

confidence: 92%

“…Recent studies found that the genetic deletion of GPR4 in mouse colitis models decreased the expression of endothelial adhesion molecules VCAM-1 and E-Selectin in the intestinal microvasculature which was associated with reduced mucosal leukocyte infiltration and intestinal inflammation [19,20]. Furthermore, GPR4 was shown to increase tissue injury in a renal ischemia-reperfusion mouse model [21].Our current study focuses on the GPR4-mediated endothelial paracellular gap formation and vessel permeability in the inflammatory response. Using genetic and pharmacological approaches, we demonstrate that activation of GPR4 by acidosis induces endothelial paracellular gap formation and permeability through the Gα12/13 signaling pathway.…”

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confidence: 95%

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confidence: 99%

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The proton-sensing GPR4 receptor regulates paracellular gap formation and permeability of vascular endothelial cells

Krewson

Sanderlin

Marie

et al. 2019

Preprint

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Tissue acidosis can be a consequence of numerous disease states including stroke, myocardial infarction, limb ischemia, and inflammation. Blood vessels existing in the affected tissues are associated with the progression of acidosis-related diseases. However, the mechanisms by which endothelial cells (ECs) lining the affected blood vessels sense and respond to an acidic microenvironment remain largely unclear. We investigated the functional effects of the proton-sensing G protein-coupled receptor GPR4 in acidosisinduced endothelial inflammation. GPR4 is highly expressed in ECs and known to regulate EC inflammation and endoplasmic reticulum stress responses within acidic microenvironments. Using genetic and pharmacological approaches, we demonstrate that GPR4 activation by acidosis increases EC paracellular gap formation and permeability.We further demonstrate that GPR4-mediated paracellular gap formation is dependent on the Gα12/13 signaling pathway. To assess the functional role of GPR4 in the inflammatory response in vivo, we utilized an acute hindlimb ischemia-reperfusion mouse model. We demonstrate that both genetic deletion and pharmacological inhibition of GPR4 reduce tissue edema, exudate formation, endothelial adhesion molecule expression, and leukocyte infiltration in the inflamed tissue. Collectively, these data suggest GPR4/Gα12/13 signaling mediates acidosis-induced endothelial paracellular gap formation and permeability. This study implicates GPR4 as a candidate therapeutic target for the remediation of inflammation and tissue edema. tissue microenvironment is associated with a wide range of inflammation-associated disease states such as arthritis, inflammatory bowel disease, myocardial infarction, stroke, and limb ischemia. Previous reports note that local pH ranging from 6.0 to 7.0 is common in the microenvironments of inflamed tissues, solid tumors, and ischemic tissues [9][10][11][12].In ischemic disease, one study demonstrated that within 50 minutes of coronary artery occlusion, local tissue extracellular pH decreased from 7.4 to 5.5 in domestic pigs [13].Furthermore, in the tourniquet-induced rabbit limb ischemia model, local tissue pH decreased rapidly within 1 hour and dropped from 7.30 to 6.36 during the 4 hour course of limb ischemia [14]. In summary, an acidic interstitial pH is an inflammatory microenvironmental factor in many pathological conditions and has been demonstrated to modulate tissue, blood vessel, and immune cell functions [9][10][11][12].Cells can sense extracellular acidification through multiple molecular sensors such as acid-sensing ion channels (ASICs), transient receptor potential (TRP), and proton-sensing G protein-coupled receptors (GPCRs) [7,11,15,16]. GPR4 is a member of the proton-sensing GPCR family, which also includes GPR65 (TDAG8) and GPR68 (OGR1) [7,11,[16][17][18]. GPR4 is highly expressed in vascular endothelial cells (ECs) and has been shown to increase the expression of inflammatory cytokines, chemokines, adhesion molecules, and ER stress related genes upon...

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 95%

mentioning

confidence: 99%

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The proton-sensing GPR4 receptor regulates paracellular gap formation and permeability of vascular endothelial cells

Krewson

Sanderlin

Marie

et al. 2019

Preprint

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“…CHOP is a basic leucine zipper transcription factor belonging to the C/EBP family of CCAATP enhancer-linked proteins. CHOP is normally expressed at a low level but is upregulated under ER stress,27 causing cell cycle arrest or apoptosis; conversely, loss of CHOP function protects cells against apoptosis 32. Our results demonstrate that GRP78 and CHOP levels were increased by OGD/R but were decreased by Tβ4 treatment.…”

Section: Discussionmentioning

confidence: 59%

<p>Thymosin β4 prevents oxygen-glucose deprivation/reperfusion-induced injury in rat cortical neurons</p>

Zhang

Liu

Huang

2019

NDT

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Purpose: This study investigated whether thymosin (T) β4 protects against oxygen-glucose deprivation/reperfusion (OGD/R) injury in rat cortical neurons, as well as the underlying mechanisms. Methods: Primary rat cortical neurons were transfected with Tβ4 overexpression plasmid; the transfection efficiency was confirmed by detecting Tβ4 expression by fluorescence quantitative PCR and Western blotting. The OGD/R model was established and apoptotic cells were quantified by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling. Structural changes in the endoplasmic reticulum were visualized by transmission electron microscopy. The expression levels of 78-kDa glucose-regulated protein (GRP) 78, C/EBP-homologous protein (CHOP), B-cell lymphoma (Bcl)-2, and Bcl-2-associated X protein (Bax) were determined by Western blotting. The effect of Tβ4 on OGD/R injury was evaluated by adding exogenous Tβ4 to neuronal cultures. Results: Cortical neurons were identified by the expression of neuron-specific enolase. In OGD/R cells, the rate of apoptosis was increased and GRP78, CHOP, and Bax were upregulated whereas Bcl-2 was downregulated relative to the control group. These effects were reversed by Tβ4 overexpression. Endoplasmic reticulum (ER) stress was observed in the OGD/R group, but this was abolished in neurons overexpressing Tβ4. The protective effect of Tβ4 against OGD/R injury was also demonstrated in cells treated with exogenous Tβ4 (10 ng/mL), which blocked OGD/R-induced apoptosis by inhibiting ER stress-related and pro-apoptotic protein expression. Conclusion: Tβ4 prevents OGD/R-induced ER stress-dependent apoptosis in cortical neurons, and is a potential treatment for cerebral ischemia-reperfusion injury.

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“…In the present study, GPR4 expression was also found to be associated with the clinicopathological features of HCC patients, indicating the involvement of GPR4 in angiogenesis, tumor growth and the development of HCC. Dong et al (46) observed that the inhibition of cell apoptosis led to decreased expression of CHOP by GPR4, following hypoxia/reoxygenation treatment in human umbilical vein ECs. Moreover, the inhibition of GPR4 resulted in decreased renal injury following ischemia-reperfusion and inhibition of cell apoptosis through the suppression of CHOP expression (46) Therefore, GPR4 has potential as a diagnostic marker for the diagnosis of liver cancer, and as a therapeutic target in HCC.…”

Section: Discussionmentioning

confidence: 99%

Association between G‑protein coupled receptor 4 expression and microvessel density, clinicopathological characteristics and survival in hepatocellular carcinoma

et al. 2020

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G-protein coupled receptor 4 (GPR4) acts as a proton-sensing receptor and plays a role in regulating angiogenesis. Endoglin/CD105 is a marker of cell proliferation in vascular endothelial cells, particularly in tumor vasculature cells. Although there have been several studies investigating angiogenesis in hepatocellular carcinoma (HCC), none have investigated the association between GPR4 and microvessel density (MVD)-CD105 in this type of cancer. In the present study, CD105 and GPR4 were found to be expressed in benign and malignant liver tissues by immunofluorescence staining and laser confocal microscopy. Compared with levels in benign tissues, CD105 and GPR4 were highly expressed in neoplastic tissues. Furthermore, the average fluorescence intensity of GPR4 and MVD-CD105 was positively correlated. GPR4 and CD105 were found to be co-localized in the vascular endothelium in tumor tissues. Furthermore, the expression of GPR4 was higher in the marginal region of tumor tissues compared with the central region. These findings suggest that the expression of GPR4 in tumor microvessels in HCC may be implicated in tumor angiogenesis and development. Furthermore, the association between the expression of GPR4 and the clinicopathological features of patients with HCC further suggests a role for GPR4 in tumor angiogenesis and growth. Overall, these results suggest the potential of GPR4 as a prognostic factor and as an antiangiogenic target in patients with HCC.

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GPR4 knockout improves renal ischemia–reperfusion injury and inhibits apoptosis via suppressing the expression of CHOP

Cited by 23 publications

References 31 publications

The proton-sensing GPR4 receptor regulates paracellular gap formation and permeability of vascular endothelial cells

The proton-sensing GPR4 receptor regulates paracellular gap formation and permeability of vascular endothelial cells

<p>Thymosin β4 prevents oxygen-glucose deprivation/reperfusion-induced injury in rat cortical neurons</p>

Association between G‑protein coupled receptor 4 expression and microvessel density, clinicopathological characteristics and survival in hepatocellular carcinoma

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